Highlights from Recent Cancer Literature
Journal: Cancer Research (2021)

MYCN amplification is a hallmark of neuroblastoma, usually in the form of extrachromosomal circular DNA (ecDNA). Helmsauer and colleagues distinguished two types of amplicons responsible for MYCN overexpression: (i) coamplification of a proximal enhancer regulated by the noradrenergic core regulatory circuit (CRC) or (ii) high complexity and lack of local MYCN-specific enhancers. Type II amplicons hijacked enhancers and insulators through the formation of neotopologically associated domains (neo-TAD). Further, Helmsauer and colleagues defined five enhancer elements responsible for MYCN expression, bound by noradrenergic CRC transcription factors. Some amplicons also contained E-boxes, indicating an additional MYC-protein regulation. The authors highlight that tissue-specific enhancers determine MYCN amplicon structure, as amplicons differ between neuroblastomas and medulloblastomas. Notably, they detected coamplification of proto-oncogenes (ODC1, GREB1, ALK) and MYCN on the same ecDNAs.Expert Commentary: This study sheds light on the complex epigenetics behind MYCN amplification in neuroblastoma, showing how enhancer hijacking and coamplification of proto-oncogenes together with regulatory regions are key aberrations in cancer.Helmsauer K, Valieva ME, Ali S, Chamorro González R, Schöpflin R, Röefzaad C, et al. Enhancer hijacking determines extrachromosomal circular MYCN amplicon architecture in neuroblastoma. Nat Commun 2020:5823. DOI: 10.1038/s41467-020-19452-y.Despite high levels of activated EGFR in triple-negative breast cancer (TNBC), targeting EGFR in TNBC has limited efficacy. Cruz-Gordillo and colleagues utilized a genome-wide CRISPR-Cas9 knockout screen to understand why EGFR inhibition is ineffective in TNBC. After demonstrating resistance to the EGFR TKI erlotinib, they identified members of the Elongator complex (ELP1-6) as essential for erlotinib resistance. Inhibition of ELP proteins sensitized to erlotinib through decreasing MCL1 expression and inducing apoptosis. Genetic or pharmacologic inhibition of MCL1 synergistically sensitized to erlotinib in TNBC cell lines.Expert Commentary: This study revealed a previously unrecognized oncogene addiction and suggests the combination of an EGFR and an MCL1 inhibitor may be an effective therapy for a subset of TNBC patients.Cruz-Gordillo P, Honeywell ME, Harper NW, Leete T, Lee MJ. ELP-dependent expression of MCL1 promotes resistance to EGFR inhibition in triple-negative breast cancer cells. Sci Signal 2020;13:eabb9820. DOI: 10.1126/scisignal.abb9820.Cell surface–associated mucin is a heterodimer, and the C-terminal subunit, MUC1-C, is aberrantly expressed in castrate-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC). MUC1-C suppresses AR axis signaling and by poorly defined mechanisms induces lineage plasticity and stemness associated with NEPC progression. Hagiwara and colleagues demonstrated that MUC1-C bound directly to the E2F1 transcription factor and that MUC1-E2F1 signaling in prostate cancer cells induced expression of embryonic stem cell-associated BAF (esBAF) chromatin remodeling components. MUC1-C also associated with BAF and activated BAF-dependent induction of the NOTCH1 effector of cancer stem cell function and the NANOG pluripotency factor, thereby driving self-renewal capacity. These findings provide support for involvement of MUC1-C in integrating the activation of E2F1 and esBAF with cancer stem cell function.Expert Commentary: That MUC1-C confers cancer stem cell lineage plasticity in CRPC/NEPC progression lends support for this oncogenic protein as a potential prognostic factor and therapeutic target in advanced intractable prostate cancer.Hagiwara M, Yasumizu Y, Yamashita N, Rajabi H, Fushimi A, Long MD, et al. MUC1-C activates the BAF (mSWI/SNF) complex in prostate cancer stem cells. Cancer Res 2021;81:1111–22.TP53 is the most commonly mutated gene in cancer, however, these alterations remain untargetable. Chen and colleagues utilized a structure-directed small molecule screen to identify arsenic trioxide (ATO) as a possible therapy to restore mutant TP53 function. ATO was shown to bind and stabilize the structural DNA binding domain but not DNA contacting mutations through three arsenic-coordinating cysteines in TP53. ATO treatment increased stability and transcriptional activity of mutant TP53 protein. ATO led to growth suppression in vitro and in vivo in a TP53 structural mutant-dependent manner in hematologic and solid tumors.Expert Commentary: This study provides the rationale for future clinical trials with ATO to potentially restore TP53 function in a subset of TP53-mutant cancers.Chen S, Wu J-L, Liang Y, Tang Y-G, Song H-X, Wu L-L, et al. Arsenic trioxide rescues structural p53 mutations through a cryptic allosteric site. Cancer Cell; Published online December 7, 2020; DOI: 10.1016/j.ccell.2020.11.013.The majority of cancer deaths can be attributed to metastasis. However, large-scale characterization of human cell lines has been limited due to the complexity of xenografts and most studies have been performed with a small number of models. Jin and colleagues performed an in vivo barcoding to determine the metastatic potential of human cancer cell lines in mouse xenografts at large scale. After optimization and analysis of reproducibility, the authors used 500 cell lines from 21 types of solid tumors. This first-generation metastasis map, MetMap, revealed organ-specific patterns that could be correlated with clinical and genomic data. Studying brain metastasis of breast cancer cells, Jin and colleagues identified changes in lipid metabolism as a common feature. Using in vivo CRISPR targeting of 29 lipid-related genes, they identified six hits that inhibited metastasis, validating the preclinical utility of the data.Expert Commentary: The MetMap can be used as a resource for identification of novel therapeutic strategies for metastatic cancers.Jin X, Demere Z, Nair K, Ali A, Ferraro GB, Natoli T, et al. A metastasis map of human cancer cell lines Nature 2020;588:331–6.Indoleamine 2,3-dioxygenase 1 (IDO1) is known to have immunosuppressive activity by breaking down tryptophan and slowing cellular translation. However, IDO inhibitor immunotherapies have failed. Bartok and colleagues demonstrated that IDO1-mediated tryptophan depletion positively affects T-cell responses to cancer. As shown previously, IFNγ induced IDO1 expression and reduced tryptophan levels in cancer cells. Ribosome profiling revealed an anticipated stalling of the ribosome at Trp codons with IFNγ treatment. Unexpectedly, stalled ribosomes “W-bumps” were also found ∼30 nucleotides downstream of these Trp residues and were dependent on IDO1 activity. W-bumps resulted from ribosomal frameshifting, generating new peptide sequences that, due to their disordered nature, became structurally stalled within the ribosome. Importantly, these novel peptide sequences produced neoantigens recognized by CD8 T cells in mouse cancer models and human patients. Thus, IFNγ-induced IDO may actually promote immune responses by generating cancer neoantigens.Expert Commentary: IFNγ-driven IDO1 activity in tumors generates novel peptides recognized by T cells by promoting ribosomal frameshifting.Bartok O, Pataskar A, Nagel R, Laos M, Goldfarb E, Hayoun D, et al. Anti-tumour immunity induces aberrant peptide presentation in melanoma. Nature; Published online December 16, 2020; DOI: 10.1038/s41586-020-03054-1.Note: Breaking Insights are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.